In the framework of this application, ischaemia is defined as the reduction or loss of blood flow to a tissue, and associated therewith, the reduction or loss of e.g. oxygen suppletion to a tissue.
In the framework of this application, ischaemic damage is defined as the adverse effects associated with an ischaemic event, such as ischaemic necrosis or infarction. The metabolic events thought to underlie such cell degeneration and cell death comprise: energy failure through ATP depletion; cellular acidosis; glutamate release; calcium ion influx; stimulation of membrane phospholipid degradation and subsequent free-fatty-acid accumulation; and free radical generation.
There is a growing need for compounds that may provide protection against ischaemia and its associated adverse effects.
It has been found recently that certain highly specific delta-2 opioid receptor agonists can provide extended pharmacological induced ischaemic protection to the myocardium by a process similar to that which occurs in ischaemic preconditioning (IPC) (Govindaswami et al., in Proceedings of the 11th International Hibernation Symposium 2000, pp. 377-384, Springer-Verlag, Berlin, Germany). Ischaemic preconditioning describes the phenomenon that a short period of ischaemia preconditions the heart such that a subsequent period of ischaemia causes less damage. In turn, this results in a smaller myocardial infarction and fewer arrhythmias. The mechanism is thought to be based on modifications in the function (opening) of the mitochondrial ATP-sensitive K-channel (mitoKATP). One known delta-2 agonist is DADLE (D-Ala2-D-Leu5-enkephalin) which has been shown to induce the same effect as ischaemic preconditioning on an organ. Therefore, the mode of action of both ischaemic preconditioning and chemical compounds must be seen as a trigger to activate a more basal or protective cellular mode. Since delta opioid receptors are found in most tissues, including heart and brain tissue, it may be expected that the compounds exerting an ischaemic protection to e.g. heart tissue, will do the same to brain tissue, and also for example, to lung, kidney of liver tissue.
At present, there are two main therapeutic areas where ischaemia plays a important role: cardiac ischaemia and cerebral ischaemia or stroke.
Cardiac Ischaemia
Cardiac surgery is always associated with controlled imposition of one or more episodes of ischaemia and reperfusion. In conventional cardiac surgery, the heart is stopped and cooled with a cardioplegic solution to reduce myocardial oxygen consumption such that it is possible to impose a longer period of ischaemia on the heart without too much damage. However, this requires maintenance of the blood circulation by a system of extra corporal circulation, which has several important drawbacks: it induces a significant inflammatory body reaction, it causes micro-embolisms and it thoroughly disturbs the coagulation and fibrinolytic system of the blood. Moreover, the micro-embolisms and non-pulsatile circulation during surgery with extra corporal circulation are responsible for suboptimal perfusion of vital organs such as the brain, kidneys and intestines. This results e.g. in an increased anaerobic metabolism (increased lactate in the postoperative period), impaired kidney function and confusion.
Owing to the development of local (mechanical) stabilizers, over the past several years, in order to avoid the aforementioned drawbacks, coronary surgery has been performed without the aid of extra corporal circulation. The disadvantage however is that the heart remains normothermic and has to perform mechanical work while regional ischaemia is imposed. At present, worldwide over 30% of coronary surgery is performed without the use of extra corporal circulation. For this application a cardioprotective agent would be extremely useful. Such an agent should be able to exert a protective action on the myocardial tissue using a basal cellular mechanism, thereby prolonging the period of imposed ischaemia.
In addition, there is a potential field of application in donor heart preservation, which is still a current problem, since the acceptable period of ischaemia is still limited to 4 to 6 hours. Also, cardiac surgery requiring complex reconstructions with long periods of intra-operative cardiac ischaemia can benefit from a cardioprotective agent in addition to the presently used cardioplegic arrest.
In general, there is a potential field of application in all surgical and percutaneous interventional procedures where the ischaemia-reperfusion sequence imposed upon any organ plays a role, such as, for example, transplant surgery, aneurysm surgery, vascular surgery for obstructive vascular disease and percutaneous interventions on stenosed coronary, carotic and peripheral arteries.
Particularly, there is a potential field of application for patients before undergoing anesthesia for any reason, in which conditions of reduced blood supply to organs apply, such as, for example in stable and unstable angina, or conditions that can be caused by the hemodynamic effects of anesthesia, such as loss of blood pressure, as well as for patients during the first hours from the onset of a hart attack before the definitive formation of blood cloths.
Cerebral Ischaemia
The brain, more than any other organ in the body, depends, for its survival and proper functioning, on a relatively constant supply of oxygenated blood. While comprising only 2% of the body's weight, the brain receives 15% of the heart's output of blood and consumes 20% of the oxygen used by the body. In addition, a constant supply of blood is required to provide the brain with glucose, the major energy substrate used by the brain to produce high energy phosphates such as ATP (see for instance WO 96/27380 (Interneuron Pharmaceuticals, Inc.)).
In the framework of this application, cerebral ischaemia is defined as the interruption or reduction of blood flow in the arteries feeding the brain, usually as a result of a blood cloth (thrombus) or other matter (embolus) occluding the arteries, resulting into an ischaemic stroke. As defined herein, ischaemic stroke is a syndrome, caused by a diverse etiologies, such as atherosclerotic cerebrovascular disease such as for example hypoperfusion and arteriogenic emboli; penetrating artery disease; cardiogenic embolism, such as, but not limited to, atrial fibrillation, valve disease and ventricular thrombi; cryptogenic stroke; and other more unusual causes, such as, for example prothrombic states, dissections, arteritis, migraine or vasospasm and drug abuse (see for instance Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology, edited by M. Verstraete, V. Fuster and E. J. Topol, Second Edition, Lippincot-Raven Publishers, Philadelphia, 1998).
Stroke is the third cause of death in the US, and about 500,000 new cases occur every year. Worldwide, stroke is the number one cause of death due to the particularly high incidence of stroke in Asia. Ischaemic stroke is the most common form of stroke and is responsible for about 85% of all strokes.
There is a potential field of application in the case of stroke prevention in certain cases, e.g. during surgery where there exists a risk for an ischaemic event, in the reduction of ischaemic damage in case of a stroke, in reducing the extent of cerebral infarction subsequent to cerebral ischaemia and in the treatment of ischaemic stroke, in particular the acute treatment of stroke after an ischaemic event.